Summary: The complement system is an important link between antigen-specific and innate immunity. Not only can it accelerate the immune destruction of foreign microbes, but recent experiments have shown that it can also play a role in initiating the response to foreign proteins. For example, antigens binding complement component C3d can increase their immunogenicity by up to 1,000-fold, as compared to the same antigen without complement. We have uncovered a mechanism by which HIV gp120 evades complement, and we are exploring the role of complement-bound gp120 in initiating the immune response or in mediating immune destruction. HIV envelope glycoprotein gp120 is heavily glycosylated, which may help the virus to evade immunity by covering up important antigenic sites. We have produced a gp120 mutant which lacks 6 out of 22 sugar sidechains, to expose these sites for immune responses and antibody binding. By itself, deglycosylation of these sites had little effect on either antibody induction or binding. However, to our surprise, the missing sugars had a profound effect on the ability of gp120 to fix complement. In the presence of antibodies, deglycosylated gp120 became 100-fold more reactive with C3d than the fully glycosylated form. In monkeys, infection with deglycosylated variants of SIV leads to control of infection, with viral burdens reduced to undetectable levels. If the mechanism was through complement-mediated destruction, this could represent an important role of innate immunity in resistance to infection. Since these animals resemble long term nonprogressors, perhaps drugs causing even partial deglycosylation of HIV could help to control viral burden in humans. Considering that glycoproteins are a common feature among many enveloped viruses, these observations could apply to a wide range of viruses. If the deglycosylated form is more susceptible to complement mediated destruction, this observation suggests a way to control infections by a wide range of biologically important pathogens.